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Frontal cortex and striatal cellular and molecular pathobiology in individuals with Down syndrome with and without dementia

  • Sylvia E. Perez
  • Jennifer C. Miguel
  • Bin He
  • Michael Malek-Ahmadi
  • Eric E. Abrahamson
  • Milos D. Ikonomovic
  • Ira Lott
  • Eric Doran
  • Melissa J. Alldred
  • Stephen D. Ginsberg
  • Elliott J. MufsonEmail author
Original Paper

Abstract

Although, by age 40, individuals with Down syndrome (DS) develop amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer’s disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD −) is under-investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as Aβ and its precursor protein (APP) to frontal cortex (FC) and striatal tissue from DSD + to DSD − cases. Expression profiling of single pS422 labeled FC layer V and VI neurons was also determined using laser capture microdissection and custom-designed microarray analysis. Analysis revealed that cortical and striatal Aβ plaque burdens were similar in DSD + and DSD − cases. In both groups, most FC plaques were neuritic, while striatal plaques were diffuse. By contrast, FC AT8-positive NFTs and neuropil thread densities were significantly greater in DSD + compared to DSD −, while striatal NFT densities were similar between groups. FC pS422-positive and TauC3 NFT densities were significantly greater than Alz50-labeled NFTs in DSD + , but not DSD − cases. Putaminal, but not caudate pS422-positive NFT density, was significantly greater than TauC3-positive NFTs. In the FC, AT8 + pS422 + Alz50, TauC3 + pS422 + Alz50, pS422 + Alz50, and TauC3 + pS422 positive NFTs were more frequent in DSD + compared to DSD- cases. Single gene-array profiling of FC pS422 positive neurons revealed downregulation of 63 of a total of 864 transcripts related to Aβ/tau biology, glutamatergic, cholinergic, and monoaminergic metabolism, intracellular signaling, cell homeostasis, and cell death in DSD + compared DSD − cases. These observations suggest that abnormal tau aggregation plays a critical role in the development of dementia in DS.

Keywords

Down syndrome Dementia Amyloid Tau Microarray Frontal cortex Striatum 

Notes

Acknowledgements

We gratefully acknowledge the contribution of Ms. L. Shao and Mr. M. Nadeem. This work was supported by the National Institute of Health (grants: P01 AG025204 and R01 AG052528 to M.D.I, R01 AG061566 to E.J.M., PPG AG014449 to E.J.M., S.D.G. and M.D.I, R01 AG043375 to S.D.G. and E.J.M., and P01 AG017617 to S.D.G.), Bright Focus Foundation (E.J.M.), and by the Arizona Alzheimer’s Consortium at Barrow Neurological Institute (S.E.P.).

Author contributions

Study concept and design: SEP and EJM. Acquisition of data: SEP, JM, EA, MM-A and BH. Analysis and interpretation of data: SEP and EJM. Drafting of the article: SEP and EJM. Critical revision of the article for important intellectual content: MDI, EA, IL, ED, SDG, and MJA. Facilitation of access to DS tissue: IL and ED. Study supervision: EJM.

Compliance with ethical standards

Ethical responsibilities

All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors declared that the manuscript has not been submitted to other journal for publication or has been published previously partly or in full. The authors report no conflict of interest.

Supplementary material

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Supplementary material 1 (DOCX 12 kb)
401_2019_1965_MOESM2_ESM.pdf (1.3 mb)
Supplementary material 2 (PDF 1308 kb)

References

  1. 1.
    Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H et al (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18:484–496PubMedPubMedCentralGoogle Scholar
  2. 2.
    Alldred MJ, Che S, Ginsberg SD (2009) Terminal continuation (TC) RNA amplification without second strand synthesis. J Neurosci Methods 177:381–385CrossRefPubMedGoogle Scholar
  3. 3.
    Amargós-Bosch M, Bortolozzi A, Puig MV, Serrats J, Adell A, Celada P et al (2004) Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex. Cereb Cortex 14:281–299CrossRefPubMedGoogle Scholar
  4. 4.
    Annus T, Wilson LR, Hong YT, Acosta-Cabronero J, Fryer TD, Cardenas-Blanco A et al (2016) The pattern of amyloid accumulation in the brains of adults with Down syndrome. Alzheimers Dement 12:538–545CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Arendt T, Stieler JT, Holzer M (2016) Tau and tauopathies. Brain Res Bull 126:238–292CrossRefPubMedGoogle Scholar
  6. 6.
    Argellati F, Massone S, d’Abramo C, Marinari UM, Pronzato MA, Domenicotti C (2006) Evidence against the overexpression of APP in Down syndrome. IUBMB Life 58:103–106CrossRefPubMedGoogle Scholar
  7. 7.
    Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1:103–116CrossRefPubMedGoogle Scholar
  8. 8.
    Bakkar RM, Luo G, Webb TA, Crutcher KA, de Courten-Myers GM (2010) Down’s syndrome with Alzheimer’s disease-like pathology: what can it teach us about the amyloid cascade hypothesis? Int J Alzheimers Dis.  https://doi.org/10.4061/2010/175818 CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Basurto-Islas G, Luna-Muñoz J, Guillozet-Bongaarts AL, Binder LI, Mena R, García-Sierra F (2008) Accumulation of aspartic acid421- and glutamic acid391-cleaved tau in neurofibrillary tangles correlates with progression in Alzheimer disease. J Neuropathol Exp Neurol 67:470–483CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259CrossRefGoogle Scholar
  11. 11.
    Braak H, Rüb U, Schultz C, Del Tredici K (2006) Vulnerability of cortical neurons to Alzheimer’s and Parkinson’s diseases. J Alzheimers Dis 9:35–44CrossRefPubMedGoogle Scholar
  12. 12.
    Che S, Ginsberg SD (2004) Amplification of RNA transcripts using terminal continuation. Lab Invest 84:131–137CrossRefPubMedGoogle Scholar
  13. 13.
    Cohen AD, McDade E, Christian B, Price J, Mathis C, Klunk W et al (2018) Early striatal amyloid deposition distinguishes Down syndrome and autosomal dominant Alzheimer’s disease from late-onset amyloid deposition. Alzheimers Dement 14:743–750CrossRefPubMedGoogle Scholar
  14. 14.
    Conrad LC, Leonard CM, Pfaff DW (1974) Connections of the median and dorsal raphe nuclei in the rat: an autoradiographic and degeneration study. J Comp Neurol 156:179–205CrossRefPubMedGoogle Scholar
  15. 15.
    Counts SE, Alldred MJ, Che S, Ginsberg SD, Mufson EJ (2014) Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology 79:172–179CrossRefPubMedGoogle Scholar
  16. 16.
    Counts SE, He B, Che S, Ikonomovic MD, DeKosky ST, Ginsberg SD et al (2007) Alpha7 nicotinic receptor up-regulation in cholinergic basal forebrain neurons in Alzheimer disease. Arch Neurol 64:1771–1776CrossRefPubMedGoogle Scholar
  17. 17.
    Counts SE, Mufson EJ (2010) Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity. J Neurochem 113:649–660CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Davidson YS, Robinson A, Prasher VP, Mann DMA (2018) The age of onset and evolution of Braak tangle stage and Thal amyloid pathology of Alzheimer’s disease in individuals with Down syndrome. Acta Neuropathol Commun 6:56CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ et al (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73:685–697CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Dekker AD, Vermeiren Y, Carmona-Iragui M, Benejam B, Videla L, Gelpi E et al (2017) Monoaminergic impairment in Down syndrome with Alzheimer’s disease compared to early-onset Alzheimer’s disease. Alzheimers Dement 10:99–111Google Scholar
  21. 21.
    DeVos SL, Corjuc BT, Oakley DH, Nobuhara CK, Bannon RN, Chase A et al (2018) Synaptic tau seeding precedes tau pathology in human Alzheimer’s Disease brain. Front Neurosci 12:267CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Flores-Rodríguez P, Ontiveros-Torres MA, Cárdenas-Aguayo MC, Luna-Arias JP, Meraz-Ríos MA, Viramontes-Pintos A et al (2015) The relationship between truncation and phosphorylation at the C-terminus of tau protein in the paired helical filaments of Alzheimer’s disease. Front Neurosci 9:33PubMedPubMedCentralGoogle Scholar
  23. 23.
    Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X et al (2000) DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet 9:1681–1690CrossRefPubMedGoogle Scholar
  24. 24.
    Galvin JE, Ginsberg SD (2004) Expression profiling and pharmacotherapeutic development in the central nervous system. Alzheimer Dis Assoc Disord 18:264–269PubMedGoogle Scholar
  25. 25.
    Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL et al (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci USA 100:10032–10037CrossRefPubMedGoogle Scholar
  26. 26.
    García-Sierra F, Ghoshal N, Quinn B, Berry RW, Binder LI (2003) Conformational changes and truncation of tau protein during tangle evolution in Alzheimer’s disease. J Alzheimers Dis 5:65–77CrossRefPubMedGoogle Scholar
  27. 27.
    Gearing M, Levey AI, Mirra SS (1997) Diffuse plaques in the striatum in Alzheimer disease (AD): relationship to the striatal mosaic and selected neuropeptide markers. J Neuropathol Exp Neurol 56:1363–1370CrossRefPubMedGoogle Scholar
  28. 28.
    Ghoshal N, García-Sierra F, Fu Y, Beckett LA, Mufson EJ, Kuret J et al (2001) Tau-66: evidence for a novel tau conformation in Alzheimer’s disease. J Neurochem 77:1372–1385CrossRefPubMedGoogle Scholar
  29. 29.
    Giménez-Barcons M, Casteràs A, del Armengol M, Porta EP, Correa PA, Marín A et al (2014) Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. J Immunol 193:3872–3879CrossRefPubMedGoogle Scholar
  30. 30.
    Ginsberg SD, Alldred MJ, Counts SE, Cataldo AM, Neve RL, Jiang Y et al (2010) Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer’s disease progression. Biol Psychiatry 68:885–893CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ginsberg SD, Che S (2004) Combined histochemical staining, RNA amplification, regional, and single cell cDNA analysis within the hippocampus. Lab Invest 84:952–962CrossRefPubMedGoogle Scholar
  32. 32.
    Ginsberg SD, Che S, Counts SE, Mufson EJ (2006) Single cell gene expression profiling in Alzheimer’s disease. NeuroRx 3:302–318CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ginsberg SD, Wuu CS, Counts JSE, Mufson EJ (2006) Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer’s disease. J Neurochem 97:475–487CrossRefPubMedGoogle Scholar
  34. 34.
    Ginsberg SD, Elarova I, Ruben M, Tan F, Counts SE, Eberwine JH et al (2004) Single-cell gene expression analysis: implications for neurodegenerative and neuropsychiatric disorders. Neurochem Res 29:1053–1064CrossRefPubMedGoogle Scholar
  35. 35.
    Ginsberg SD, Hemby SE, Lee VM, Eberwine JH, Trojanowski JQ (2000) Expression profile of transcripts in Alzheimer’s disease tangle-bearing CA1 neurons. Ann Neurol 48:77–87CrossRefPubMedGoogle Scholar
  36. 36.
    Ginsberg SD, Malek-Ahmadi MH, Alldred MJ, Che S, Elarova I, Chen Y et al (2017) Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer’s disease. Hippocampus.  https://doi.org/10.1002/hipo.22802 CrossRefPubMedGoogle Scholar
  37. 37.
    Glasson EJ, Sullivan SG, Hussain R, Petterson BA, Montgomery PD, Bittles AH (2002) The changing survival profile of people with Down’s syndrome: implications for genetic counselling. Clin Genet 62:390–393CrossRefPubMedGoogle Scholar
  38. 38.
    Goedert M, Jakes R, Vanmechelen E (1995) Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205. Neurosci Lett 189:167–169CrossRefPubMedGoogle Scholar
  39. 39.
    Guedj F, Pennings JL, Massingham LJ, Wick HC, Siegel AE, Tantravahi U et al (2016) An integrated human/murine transcriptome and pathway approach to identify prenatal treatments for Down syndrome. Sci Rep. https://www.nature.com/articles/srep32353
  40. 40.
    Guillozet-Bongaarts AL, Cahill ME, Cryns VL, Reynolds MR, Berry RW, Binder LI (2006) Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo. J Neurochem 97:1005–10014CrossRefPubMedGoogle Scholar
  41. 41.
    Guillozet-Bongaarts AL, Garcia-Sierra F, Reynolds MR, Horowitz PM, Fu Y, Wang T et al (2005) Tau truncation during neurofibrillary tangle evolution in Alzheimer’s disease. Neurobiol Aging 26:1015–1022CrossRefPubMedGoogle Scholar
  42. 42.
    Gyure KA, Durham R, Stewart WF, Smialek JE, Troncoso JC (2001) Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Arch Pathol Lab Med 125:489–492PubMedGoogle Scholar
  43. 43.
    Hamlett ED, Goetzl EJ, Ledreux A, Vasilevko V, Boger HA, LaRosa A et al (2017) Neuronal exosomes reveal Alzheimer’s disease biomarkers in Down syndrome. Alzheimers Dement 13:541–549CrossRefPubMedGoogle Scholar
  44. 44.
    Handen BL, Cohen AD, Channamalappa U, Bulova P, Cannon SA, Cohen WI et al (2012) Imaging brain amyloid in nondemented young adults with Down syndrome using Pittsburgh compound B. Alzheimers Dement 8:496–501CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Hartley SL, Handen BL, Devenny DA, Hardison R, Mihaila I, Price JC et al (2014) Cognitive functioning in relation to brain amyloid-β in healthy adults with Down syndrome. Brain 137:2556–2563CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Head E, Lott IT, Wilcock DM, Lemere CA (2016) Aging in Down syndrome and the development of Alzheimer’s disease neuropathology. Curr Alzheimer Res 13:18–29CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hof PR, Bouras C, Perl DP, Sparks DL, Mehta N, Morrison JH (1995) Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down’s syndrome. Quantitative regional analysis and comparison with Alzheimer’s disease. Arch Neurol 52:379–391CrossRefPubMedGoogle Scholar
  48. 48.
    Hu W, Zhang X, Tung YC, Xie S, Liu F, Iqbal K (2016) Hyperphosphorylation determines both the spread and the morphology of tau pathology. Alzheimers Dement 12:1066–1077CrossRefPubMedGoogle Scholar
  49. 49.
    Ikonomovic MD, Abrahamson EE, Isanski BA, Debnath ML, Mathis CA, Dekosky ST et al (2006) X-34 labeling of abnormal protein aggregates during the progression of Alzheimer’s disease. Methods Enzymol 412:123–144CrossRefPubMedGoogle Scholar
  50. 50.
    Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND et al (2008) Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain 131:1630–1645CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Ishibashi K, Ishiwata K, Toyohara J, Murayama S, Ishii K (2014) Regional analysis of striatal and cortical amyloid deposition in patients with Alzheimer’s disease. Eur J Neurosci 40:2701–2706CrossRefPubMedGoogle Scholar
  52. 52.
    Iulita MF, Do Carmo S, Ower AK, Fortress AM, Flores Aguilar L, Hanna M et al (2014) Nerve growth factor metabolic dysfunction in Down’s syndrome brains. Brain 137:860–872CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Iulita MF, Ower A, Barone C, Pentz R, Gubert P, Romano C et al (2016) An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: relation to cognitive decline and longitudinal evaluation. Alzheimers Dement 12:1132–1148CrossRefPubMedGoogle Scholar
  54. 54.
    Jennings D, Seibyl J, Sabbagh M, Lai F, Hopkins W, Bullich S (2015) Age dependence of brain β-amyloid deposition in Down syndrome: an [18F]florbetaben PET study. Neurology 84:500–507CrossRefPubMedGoogle Scholar
  55. 55.
    Jones BE, Moore RY (1977) Ascending projections of the locus coeruleus in the rat. II autoradiographic study. Brain Res 127:25–53PubMedGoogle Scholar
  56. 56.
    Jones EL, Hanney M, Francis PT, Ballard CG (2009) Amyloid beta concentrations in older people with Down syndrome and dementia. Neurosci Lett 451:162–164CrossRefPubMedGoogle Scholar
  57. 57.
    Kanaan NM, Morfini GA, LaPointe NE, Pigino GF, Patterson KR, Song Y et al (2011) Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J Neurosci 31:9858–9868CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Kemppainen NM, Aalto S, Wilson IA, Någren K, Helin S, Brück A et al (2006) Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease. Neurology 67:1575–1580CrossRefPubMedGoogle Scholar
  59. 59.
    Kida E, Choi-Miura NH, Wisniewski KE (1995) Deposition of apolipoproteins E and J in senile plaques is topographically determined in both Alzheimer’s disease and Down’s syndrome brain. Brain Res 685:211–216CrossRefPubMedGoogle Scholar
  60. 60.
    Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP et al (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B. Ann Neurol 55:306–319CrossRefPubMedGoogle Scholar
  61. 61.
    Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK et al (2007) Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci 27:6174–6184CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Koivunen J, Verkkoniemi A, Aalto S, Paetau A, Ahonen JP, Viitanen M et al (2008) PET amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer’s disease. Brain 131:1845–1853CrossRefGoogle Scholar
  63. 63.
    Landt J, D’Abrera JC, Holland AJ, Aigbirhio FI, Fryer TD, Canales R et al (2011) Using positron emission tomography and Carbon 11-labeled Pittsburgh compound B to image brain fibrillar β-amyloid in adults with down syndrome: safety, acceptability, and feasibility. Arch Neurol 68:890–896CrossRefPubMedGoogle Scholar
  64. 64.
    Lao PJ, Betthauser TJ, Hillmer AT, Price JC, Klunk WE, Mihaila I et al (2016) The effects of normal aging on amyloid-β deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B. Alzheimers Dement 12:380–390CrossRefPubMedGoogle Scholar
  65. 65.
    Lao PJ, Handen BL, Betthauser TJ, Mihaila I, Hartley SL, Cohen AD et al (2017) Longitudinal changes in amyloid positron emission tomography and volumetric magnetic resonance imaging in the nondemented Down syndrome population. Alzheimers Dement (Amst) 9:1–9Google Scholar
  66. 66.
    Lao PJ, Handen BL, Betthauser TJ, Mihaila I, Hartley SL, Cohen AD et al (2018) Alzheimer-like pattern of hypometabolism emerges with elevated amyloid-β burden in Down syndrome. J Alzheimers Dis 61:631–644CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Lee NC, Yang SY, Chieh JJ, Huang PT, Chang LM, Chiu YN et al (2017) Blood beta-amyloid and tau in Down syndrome: a comparison with Alzheimer’s disease. Front Aging Neurosci.  https://doi.org/10.3389/fnagi.2016.00316 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APOE in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3:16–32CrossRefPubMedGoogle Scholar
  69. 69.
    Leverenz JB, Raskind MA (1998) Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis. Exp Neurol 150:296–304CrossRefPubMedGoogle Scholar
  70. 70.
    LeVine H 3rd, Spielmann HP, Matveev S, Cauvi FM, Murphy MP, Beckett TL et al (2017) Down syndrome: age-dependence of PiB binding in postmortem frontal cortex across the lifespan. Neurobiol Aging 54:163–169CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Liao CY, Kennedy BK (2016) SIRT6, oxidative stress, and aging. Cell Res 26:143–144CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Liu F, Liang Z, Wegiel J, Hwang YW, Iqbal K, Grundke-Iqbal I et al (2008) Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J 22:3224–3233CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Lockstone HE, Harris LW, Swatton JE, Wayland MT, Holland AJ, Bahn S (2007) Gene expression profiling in the adult Down syndrome brain. Genomics 90:647–660CrossRefPubMedGoogle Scholar
  74. 74.
    Lombard DB (2009) Sirtuins at the breaking point: sIRT6 in DNA repair. Aging 1:12–16CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Mahady L, Nadeem M, Malek-Ahmadi M, Chen K, Perez SE et al (2018) HDAC2 dysregulation in the nucleus basalis of Meynert during the progression of Alzheimer’s disease. Neuropathol Appl Neurobiol 45:122.  https://doi.org/10.1111/nan.12518 CrossRefGoogle Scholar
  76. 76.
    Mann DM, Esiri MM (1989) The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s syndrome. J Neurol Sci 89:169–179CrossRefPubMedGoogle Scholar
  77. 77.
    Mann DM, Iwatsubo T (1996) Diffuse plaques in the cerebellum and corpus striatum in Down’s syndrome contain amyloid beta protein (A beta) only in the form of A beta 42(43). Neurodegeneration 5:115–120CrossRefGoogle Scholar
  78. 78.
    Mann DM, Prinja D, Davies CA, Ihara Y, Delacourte A, Défossez A et al (1989) Immunocytochemical profile of neurofibrillary tangles in Down’s syndrome patients of different ages. J Neurol Sci 92:247–260CrossRefPubMedGoogle Scholar
  79. 79.
    Mann DM, Yates PO, Hawkes J (1983) The pathology of the human locus ceruleus. Clin Neuropathol 2:1–7PubMedGoogle Scholar
  80. 80.
    Mann DM, Yates PO, Marcyniuk B (1984) Alzheimer’s presenile dementia, senile dementia of Alzheimer type and Down’s syndrome in middle age form an age related continuum of pathological changes. Neuropathol Appl Neurobiol 10:185–207CrossRefPubMedGoogle Scholar
  81. 81.
    Mann DM, Yates PO, Marcyniuk B, Ravindra CR (1986) The topography of plaques and tangles in Down’s syndrome patients of different ages. Neuropathol Appl Neurobiol 12:447–457CrossRefPubMedGoogle Scholar
  82. 82.
    Mann DM, Yates PO, Marcyniuk B, Ravindra CR (1987) Loss of neurones from cortical and subcortical areas in Down’s syndrome patients at middle age. Quantitative comparisons with younger Down’s patients and patients with Alzheimer’s disease. J Neurol Sci 80:79–89CrossRefPubMedGoogle Scholar
  83. 83.
    Margallo-Lana ML, Moore PB, Kay DW, Perry RH, Reid BE, Berney TP et al (2007) Fifteen-year follow-up of 92 hospitalized adults with Down’s syndrome: incidence of cognitive decline, its relationship to age and neuropathology. J Intellect Disabil Res 51:463–477CrossRefPubMedGoogle Scholar
  84. 84.
    Matthews DC, Lukic AS, Andrews RD, Marendic B, Brewer J, Rissman RA et al (2016) Dissociation of Down syndrome and Alzheimer’s disease effects with imaging. Alzheimers Dement (N Y) 2:69–81Google Scholar
  85. 85.
    McDade E, Kim A, James J, Sheu LK, Kuan DC, Minhas D et al (2014) Cerebral perfusion alterations and cerebral amyloid in autosomal dominant Alzheimer disease. Neurology 83:710–717CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Mesulam MM (2013) Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer’s disease. J Comp Neurol 521:4124–4144CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Mesulam MM, Geula C (1991) Acetylcholinesterase-rich neurons of the human cerebral cortex: cytoarchitectonic and ontogenetic patterns of distribution. J Comp Neurol 306:193–220CrossRefPubMedGoogle Scholar
  88. 88.
    Mesulam MM, Mufson EJ, Levey AI, Wainer BH (1983) Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol 214:170–197CrossRefPubMedGoogle Scholar
  89. 89.
    Miner LA, Backstrom JR, Sanders-Bush E, Sesack SR (2003) Ultrastructural localization of serotonin2A receptors in the middle layers of the rat prelimbic prefrontal cortex. Neuroscience 116:107–117CrossRefPubMedGoogle Scholar
  90. 90.
    Mondragón-Rodríguez S, Basurto-Islas G, Santa-Maria I, Mena R, Binder LI, Avila J et al (2008) Cleavage and conformational changes of tau protein follow phosphorylation during Alzheimer’s disease. Int J Exp Pathol 89:81–90CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Mondragón-Rodríguez S, Mena R, Binder LI, Smith MA, Perry G, García-Sierra F (2008) Conformational changes and cleavage of tau in Pick bodies parallel the early processing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol 34:62–75PubMedGoogle Scholar
  92. 92.
    Mondragón-Rodríguez S, Perry G, Luna-Muñoz J, Acevedo-Aquino MC, Williams S (2014) Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer’s disease and Down syndrome. Neuro Appl Neurobiol 40:121–135CrossRefGoogle Scholar
  93. 93.
    Motte J, Williams RS (1989) Age-related changes in the density and morphology of plaques and neurofibrillary tangles in Down syndrome brain. Acta Neuropathol 77:535–546CrossRefPubMedGoogle Scholar
  94. 94.
    Mufson EJ, Counts SE, Ginsberg SD (2002) Gene expression profiles of cholinergic nucleus basalis neurons in Alzheimer’s disease. Neurochem Res 27:1035–1048CrossRefPubMedGoogle Scholar
  95. 95.
    Mufson EJ, He B, Ginsberg SD, Carper BA, Bieler GS, Crawford F et al (2018) Gene profiling of nucleus basalis tau containing neurons in chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study. J Neurotrauma 35:1260–1271CrossRefPubMedGoogle Scholar
  96. 96.
    Mufson EJ, Perez SE, Nadeem M, Mahady L, Kanaan NM, Abrahamson EE et al (2016) Progression of tau pathology within cholinergic nucleus basalis neurons in chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study. Brain Inj 30:1399–1413CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Ni R, Gillberg PG, Bogdanovic N, Viitanen M, Myllykangas L, Nennesmo I (2017) Amyloid tracers binding sites in autosomal dominant and sporadic Alzheimer’s disease. Alzheimers Dement 13:419–430CrossRefPubMedGoogle Scholar
  99. 99.
    Nicholls SB, DeVos SL, Commins C, Nobuhara C, Bennett RE, Corjuc DL et al (2017) Characterization of TauC3 antibody and demonstration of its potential to block tau propagation. PLoS One 12:e0177914CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    O’Hearn E, Molliver ME (1984) Organization of raphe-cortical projections in rat: a quantitative retrograde study. Brain Res Bull 13:709–726CrossRefPubMedGoogle Scholar
  101. 101.
    Olson L, Fuxe K (1971) On the projections from the locus coeruleus noradrenaline neurons: the cerebellar innervation. Brain Res 28:165–171CrossRefPubMedGoogle Scholar
  102. 102.
    Patterson KR, Remmers C, Fu Y, Brooker S, Kanaan NM, Vana L et al (2011) Characterization of prefibrillar Tau oligomers in vitro and in Alzheimer disease. J Biol Chem 286:23063–23076CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Perez SE, Getova DP, He B, Counts SE, Geula C, Desire L et al (2012) Rac1b increases with progressive tau pathology within cholinergic nucleus basalis neurons in Alzheimer’s disease. Am J Pathol 180:526–540CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Perez SE, He B, Nadeem M, Wuu J, Scheff SW, Abrahamson EE et al (2015) Resilience of precuneus neurotrophic signaling pathways despite amyloid pathology in prodromal Alzheimer’s disease. Biol Psychiatry 77:693–703CrossRefPubMedGoogle Scholar
  105. 105.
    Perez SE, Raghanti MA, Hof PR, Kramer L, Ikonomovic MD, Lacor PN et al (2013) Alzheimer’s disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla). J Comp Neurol 521:4318–4338CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Perez SE, Sherwood CC, Cranfield MR, Erwin JM, Mudakikwa A, Hof PR et al (2016) Early Alzheimer’s disease-type pathology in the frontal cortex of wild mountain gorillas (Gorilla beringei beringei). Neurobiol Aging 39:195–201CrossRefPubMedGoogle Scholar
  107. 107.
    Picciotto MR, Higley MJ, Mineur YS (2012) Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron 76:116–129CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Rafii MS, Lukic AS, Andrews RD, Brewer J, Rissman RA, Strother SC et al (2017) Down Syndrome biomarker initiative and the Alzheimer’s disease neuroimaging initiative. PET Imaging of tau pathology and relationship to amyloid, longitudinal MRI, and cognitive change in Down syndrome: results from the Down syndrome biomarker initiative (DSBI). J Alzheimers Dis 60:439–450CrossRefPubMedGoogle Scholar
  109. 109.
    Remes AM, Laru L, Tuominen H, Aalto S, Kemppainen N, Mononen H et al (2008) Carbon 11-labeled Pittsburgh compound B positron emission tomographic amyloid imaging in patients with APP locus duplication. Arch Neurol 65:540–544CrossRefPubMedGoogle Scholar
  110. 110.
    Rissman RA, Poon WW, Blurton-Jones M, Oddo S, Torp R, Vitek MP et al (2004) Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114:121–130CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, Almkvist O, Farid K, Schöll M et al (2016) Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain 139:922–936CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Sabbagh MN, Chen K, Rogers J, Fleisher AS, Liebsack C, Bandy D et al (2015) Florbetapir PET, FDG PET, and MRI in Down syndrome individuals with and without Alzheimer’s dementia. JAMA Neurol 72:571–581CrossRefGoogle Scholar
  113. 113.
    Sandhu P, Naeem MM, Lu C, Kumarathasan P, Gomes J, Basak A (2017) Ser422 phosphorylation blocks human Tau cleavage by caspase-3: biochemical implications to Alzheimer’s disease. Bioorg Med Chem Lett 27:642–652CrossRefPubMedGoogle Scholar
  114. 114.
    Santana N, Artigas F (2017) Laminar and cellular distribution of monoamine receptors in rat medial prefrontal cortex. Front Neuroanat 11:87CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Sauerbeck J, Ishii K, Hosokawa C, Kaida H, Scheiwein FT, Hanaoka K et al (2018) The correlation between striatal and cortical binding ratio of 11C-PiB-PET in amyloid-uptake-positive patients. Ann Nucl Med 32:398–403CrossRefPubMedGoogle Scholar
  116. 116.
    Schöll M, Wall A, Thordardottir S, Ferreira D, Bogdanovic N, Långström B et al (2012) Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers. Neurology 79:229–236CrossRefPubMedGoogle Scholar
  117. 117.
    Schupf N, Patel B, Silverman W, Zigman WB, Zhong N, Tycko B et al (2001) Elevated plasma amyloid β-peptide 1–42 and onset of dementia in adults with Down syndrome. Neurosci Lett 301:199–203CrossRefPubMedGoogle Scholar
  118. 118.
    Schupf N, Sergievsky GH (2002) Genetic and host factors for dementia in Down’s syndrome. Br J Psychiatry 180:405–410CrossRefPubMedGoogle Scholar
  119. 119.
    Schupf N, Zigman WB, Tang MX, Pang D, Mayeux R, Mehta P et al (2010) Change in plasma Aβ peptides and onset of dementia in adults with Down syndrome. Neurology 75:1639–1644CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Sebastián C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L et al (2012) The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151:1185–1199CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1:a006189CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Shackleton B, Crawford F, Bachmeier C (2017) Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer’s disease. Curr Alzheimer Res 14:1578–1585CrossRefGoogle Scholar
  123. 123.
    Shaw JL, Zhang S, Chang KT (2015) Bidirectional regulation of amyloid precursor protein-induced memory defects by nebula/DSCR1: a protein upregulated in Alzheimer’s disease and Down syndrome. J Neurosci 35:11374–11383CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Sheehan R, Sinai A, Bass N, Blatchford P, Bohnen I, Bonell S et al (2015) Dementia diagnostic criteria in Down syndrome. Int J Geriatr Psychiatry 30:857–863CrossRefPubMedGoogle Scholar
  125. 125.
    Sontag E, Nunbhakdi-Craig V, Lee G, Brandt R, Kamibayashi C, Kuret J et al (1999) Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies. J Biol Chem 274:25490–25498CrossRefPubMedGoogle Scholar
  126. 126.
    Styren SD, Hamilton RL, Styren GC, Klunk WE (2000) X-34, a fluorescent derivative of congo red: a novel histochemical stain for Alzheimer’s disease pathology. J Histochem Cytochem 48:1223–1232CrossRefPubMedGoogle Scholar
  127. 127.
    Teller JK, Russo C, DeBusk LM, Angelini G, Zaccheo D, Dagna-Bricarelli F et al (1996) Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down’s syndrome. Nat Med 2:93–95CrossRefPubMedGoogle Scholar
  128. 128.
    Tiernan CT, Ginsberg SD, Guillozet-Bongaarts AL, Ward SM, He B, Kanaan NM et al (2016) Protein homeostasis gene dysregulation in pretangle-bearing nucleus basalis neurons during the progression of Alzheimer’s disease. Neurobiol Aging 42:80–90CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Tiernan CT, Mufson EJ, Kanaan NM, Counts SE (2018) Tau oligomer pathology in nucleus basalis neurons during the progression of Alzheimer disease. J Neuropathol Exp Neurol 77:246–259CrossRefPubMedGoogle Scholar
  130. 130.
    Tudorascu DL, Anderson SJ, Minhas DS, Yu Z, Comer D, Lao P et al (2019) Comparison of longitudinal Aβ in nondemented elderly and Down syndrome. Neurobiol Aging 73:171–176CrossRefPubMedGoogle Scholar
  131. 131.
    Vana L, Kanaan NM, Ugwu IC, Wuu J, Mufson EJ, Binder LI (2011) Progression of tau pathology in cholinergic Basal forebrain neurons in mild cognitive impairment and Alzheimer’s disease. Am J Pathol 179:2533–2550CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Villemagne VL, Ataka S, Mizuno T, Brooks WS, Wada Y, Kondo M et al (2009) High striatal amyloid beta-peptide deposition across different autosomal Alzheimer disease mutation types. Arch Neurol 66:1537–1544CrossRefPubMedGoogle Scholar
  133. 133.
    Ward SM, Himmelstein DS, Lancia JK, Binder LI (2012) Tau oligomers and tau toxicity in neurodegenerative disease. Biochem Soc Trans 40:667–671CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Wegiel J, Dowjat K, Kaczmarski W, Kuchna I, Nowicki K, Frackowiak J et al (2008) The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome. Acta Neuropathol 116:391–407CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 17:278–282CrossRefPubMedGoogle Scholar
  136. 136.
    Yates CM, Simpson J, Maloney AF, Gordon A, Reid AH (1980) Alzheimer-like cholinergic deficiency in Down syndrome. Lancet 2:979CrossRefPubMedGoogle Scholar
  137. 137.
    Zigman WB, Devenny DA, Krinsky-McHale SJ, Jenkins EC, Urv TK, Weigel J et al (2008) Alzheimer’s disease in adults with Down Syndrome. Int Rev Res Ment Retard 36:103–145CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Zigman WB, Lott IT (2007) Alzheimer’s disease in Down syndrome: neurobiology and risk. Ment Retard Dev Disabil Res Rev 13:237–246CrossRefPubMedGoogle Scholar
  139. 139.
    Zigman WB, Schupf N, Urv T, Zigman A, Silverman W (2002) Incidence and temporal patterns of adaptive behavior change in adults with mental retardation. Am J Ment Retard 107:161–174CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sylvia E. Perez
    • 1
    • 2
  • Jennifer C. Miguel
    • 1
  • Bin He
    • 1
  • Michael Malek-Ahmadi
    • 3
  • Eric E. Abrahamson
    • 4
    • 5
  • Milos D. Ikonomovic
    • 4
    • 5
  • Ira Lott
    • 6
  • Eric Doran
    • 6
  • Melissa J. Alldred
    • 7
    • 8
  • Stephen D. Ginsberg
    • 7
    • 8
    • 9
  • Elliott J. Mufson
    • 1
    Email author
  1. 1.Department of Neurobiology and NeurologyBarrow Neurological InstitutePhoenixUSA
  2. 2.School of Life Sciences, College of Liberal Arts and SciencesArizona State UniversityTempeUSA
  3. 3.Banner Alzheimer’s InstitutePhoenixUSA
  4. 4.Geriatric Research Education and Clinical CenterVA Pittsburgh Healthcare SystemPittsburghUSA
  5. 5.Departments of Neurology and PsychiatryUniversity of PittsburghPittsburghUSA
  6. 6.Departments of Pediatrics and NeurologyUniversity of CaliforniaIrvineUSA
  7. 7.Center for Dementia ResearchNathan Kline InstituteOrangeburgUSA
  8. 8.Departments of PsychiatryNYU Neuroscience Institute, NYU Langone Medical CenterNew YorkUSA
  9. 9.Departments of Neuroscience and PhysiologyThe NYU Neuroscience Institute, NYU Langone Medical CenterNew YorkUSA

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